Stromnes Ingunn M, Schmitt Thomas M, Hulbert Ayaka, Brockenbrough J Scott, Nguyen Hieu, Cuevas Carlos, Dotson Ashley M, Tan Xiaoxia, Hotes Jennifer L, Greenberg Philip D, Hingorani Sunil R
Clinical Research Division, Seattle, WA, 98109.
Department of Immunology, University of Washington School of Medicine, Seattle, WA, 98195.
Cancer Cell. 2015 Nov 9;28(5):638-652. doi: 10.1016/j.ccell.2015.09.022. Epub 2015 Oct 29.
Pancreatic ductal adenocarcinomas (PDAs) erect physical barriers to chemotherapy and induce multiple mechanisms of immune suppression, creating a sanctuary for unimpeded growth. We tested the ability of T cells engineered to express an affinity-enhanced T cell receptor (TCR) against a native antigen to overcome these barriers in a genetically engineered model of autochthonous PDA. Engineered T cells preferentially accumulate in PDA and induce tumor cell death and stromal remodeling. However, tumor-infiltrating T cells become progressively dysfunctional, a limitation successfully overcome by serial T cell infusions that resulted in a near-doubling of survival without overt toxicities. Similarly engineered human T cells lyse PDA cells in vitro, further supporting clinical advancement of this TCR-based strategy for the treatment of PDA.
胰腺导管腺癌（PDA）对化疗形成物理屏障，并诱导多种免疫抑制机制，为肿瘤的不受阻碍生长创造了一个庇护所。我们在一个原位PDA的基因工程模型中测试了经基因工程改造以表达针对天然抗原的亲和力增强型T细胞受体（TCR）的T细胞克服这些屏障的能力。工程化T细胞优先在PDA中积累，并诱导肿瘤细胞死亡和基质重塑。然而，肿瘤浸润性T细胞逐渐功能失调，通过连续输注T细胞成功克服了这一限制，使生存率几乎提高了一倍，且无明显毒性。同样经过基因工程改造的人类T细胞在体外可裂解PDA细胞，进一步支持了这种基于TCR的PDA治疗策略的临床推进。
